Diseases of Wnt signaling

Johnson, Mark; Rajamannan, Nalini M.

doi:10.1007/s11154-006-9003-3

Cited by 114 publications

(76 citation statements)

References 96 publications

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“…[1][2][3][4]17 Controlling the differentiation of these cells may, therefore, represent a strategy to treat these diseases. The results presented herein suggest that the inappropriate activation of Wnt signaling drives the chondrogenic differentiation of progenitor cells present in the walls of blood vessels.…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-Catenin Signaling Stimulates Chondrogenic and Inhibits Adipogenic Differentiation of Pericytes

Kirton

Crofts

George

et al. 2007

Circulation Research

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Abstract-The aberrant differentiation of pericytes along the adipogenic, chondrogenic, and osteogenic lineages may contribute to the development and progression of several vascular diseases, including atherosclerosis and calcific vasculopathies. However, the mechanisms controlling pericyte differentiation and, in particular, adipogenic and chondrogenic differentiation are poorly defined. Wnt/␤-catenin signaling regulates cell differentiation during embryonic and postnatal development, and there is increasing evidence that it is involved in vascular pathology. Therefore, this study tested the hypothesis that Wnt/␤-catenin signaling regulates the chondrogenic and adipogenic differentiation of pericytes. We demonstrate that pericytes express several Wnt receptors, including LDL receptor-related proteins 5 and 6, and Frizzled 1 to 4 and 7, 8, and 10, and that Wnt/␤-catenin signaling is stimulated by both Wnt3a and LiCl. Furthermore, induction of Wnt/␤-catenin signaling by LiCl enhances chondrogenesis in pericyte pellet cultures in the presence of transforming growth factor-␤3, as demonstrated by increased Sox-9 expression and glycosaminoglycan accumulation into the matrix. In contrast, transduction of pericytes with a recombinant adenovirus encoding dominant-negative T-cell factor-4 (RAd/dnTCF), which blocks Wnt/␤-catenin signaling, inhibited chondrogenesis, leading to reduced Sox-9 and type II collagen expression and less glycosaminoglycan accumulation. Together, these data demonstrate that transforming growth factor-␤3 induces the chondrogenic differentiation of pericytes by inducing Wnt/␤-catenin signaling and T-cell factor-induced gene transcription. Induction of Wnt/␤-catenin signaling also attenuates adipogenic differentiation of pericytes in both pellet and monolayer cultures, as demonstrated by decreased staining with oil red O and reduced peroxisome proliferator-activated receptor ␥2 expression. This effect was negated by transduction of pericytes with RAd/dnTCF. Together, these results demonstrate that Wnt/␤-catenin signaling inhibits adipogenic and enhances chondrogenic differentiation of pericytes. (Circ Res. 2007;101:581-589.)Key Words: pericytes Ⅲ differentiation Ⅲ Wnt signaling Ⅲ chondrogenesis Ⅲ vascular disease T here is compelling evidence that cells with multilineage potential (pericytes, calcifying vascular cells, smooth muscle cells, and adventitial myofibroblasts) are present within the walls of blood vessels and that the aberrant differentiation of these cells contributes to the development and progression of several vascular pathologies. 1-9 For example, the acquisition of an adipogenic phenotype by some populations of vascular smooth muscle cells is thought to contribute both to the development of atherosclerotic lesions and to plaque instability. 9 On the other hand, the differentiation of vascular progenitor cells into chondrocytes and osteoblasts is thought to result in the deposition of cartilage and bone in the blood vessel wall. [1][2][3][4][5][6][7][8] This latter process, which has b...

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Section: Discussionmentioning

confidence: 99%

Wnt/β-Catenin Signaling Stimulates Chondrogenic and Inhibits Adipogenic Differentiation of Pericytes

Kirton

Crofts

George

et al. 2007

Circulation Research

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“…1,3 Mounting evidence suggests that canonical Wnt signaling is central to normal skeletogenesis [4][5][6] and cancer-related bone diseases. 7,8 The first direct evidence of a role for Wnt signaling in human bone formation came from observations that inactivating mutations of the LRP5 gene, a coreceptor for Wnt, causes a syndrome associated with early-onset osteoporosis. 9 Subsequently, it was shown that a separate and distinct mutation in the same gene results in high bone density.…”

Section: Introductionmentioning

confidence: 99%

Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth

Qiang

Shaughnessy

Yaccoby

2008

Blood

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IntroductionWnts comprise a highly conserved family of secreted glycoproteins, consisting of 19 members, that bind to the Frizzled receptors alone or complexed with the low-density lipoprotein receptorrelated proteins (LRPs) 5/6. In vertebrates, Wnts can activate a "canonical" ␤-catenin-dependent pathway or several ␤-cateninindependent "noncanonical" pathways. 1,2 The canonical pathway is normally repressed at several levels. An intracellular complex, including GSK-3, axin, and the tumor suppressor gene product APC, functions to phosphorylate ␤-catenin, which in turn targets it for ubiquitin-mediated proteasomal degradation. On Wnt binding, ␤-catenin degradation is blocked, leading to its accumulation and translocation to the nucleus, where it binds the TCF/LEF family of transcription repressors, turning them into transcriptional activators. 1,3 Mounting evidence suggests that canonical Wnt signaling is central to normal skeletogenesis 4-6 and cancer-related bone diseases. 7,8 The first direct evidence of a role for Wnt signaling in human bone formation came from observations that inactivating mutations of the LRP5 gene, a coreceptor for Wnt, causes a syndrome associated with early-onset osteoporosis. 9 Subsequently, it was shown that a separate and distinct mutation in the same gene results in high bone density. 10,11 Expression of Wnt10b in transgenic mice increases bone mass, 12 and overexpression of Wnt7B and ␤-catenin in C3H10T1/2 osteoblastic precursor cells induces their differentiation into mature osteoblasts. 13,14 Osteoclastogenesis is primarily regulated by receptor activator of the NF-B ligand (RANKL) binding to RANK on the surface of osteoclast precursor cells. The ability of RANKL to bind RANK, and hence promote osteoclast development, is tightly regulated by the RANKL decoy receptor, osteoprotegerin (OPG). 15,16 Remarkably, recent studies have shown that Wnt signaling in cells of the osteoblast lineage positively regulates the expression of OPG 17,18 while negatively regulating RANKL. 19 Taken together these studies suggest that Wnt signaling is likely to be a central regulator of bone remodeling through its direct effects on osteoblastogenesis and indirect effects on osteoclastogenesis.Multiple myeloma (MM) is a malignancy of antibody-secreting plasma cells that specifically accumulate in the bone marrow (BM) but not other organs. This bone tropism suggests that the BM provides a unique microenvironment of growth and survival signals for MM cells. MM, but not its benign precursor condition, monoclonal gammopathy of undetermined significance (MGUS), is characterized by osteolytic bone disease, which can be traced to an uncoupling of bone remodeling as a result of increased osteoclast activity and decreased osteoblast activity. [20][21][22] During the past 3 decades numerous experimental and clinical studies have focused on the role of osteoclast in the osteolytic phenotype, and numerous factors associated with increased osteoclast activity in MM have been identified. 23 We recently found that MM t...

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“…Esta via é ativada pela interação da glicoproteína WNT com seu receptor, formado pela junção da proteína Frizzled com proteínas da família LRP (low-density lipoprotein receptor-related protein), o que gera o acúmulo da proteína beta-catenina (também conhecida como CTNNB1) (JOHNSON; RAJAMANNAN, 2006). Uma vez livre, a Beta-catenina migra para o núcleo, onde interage com os fatores de transcrição como LEF (Lymphoid enhancer fator) (BEHRENS et al, 1996) …”

Section: Via Wingless (Wnt)unclassified

Meduloblastoma: aspectos histológicos, moleculares e imunopatológicos

Clébis

Pinheiro

Martins

et al. 2015

Semin. Cienc. Biol. Saude

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O meduloblastoma é um tumor cerebelar caracterizado como tumor neuroectodérmico primitivo prevalente em crianças, sendo as do sexo masculinos as mais afetadas. Com relação à classificação histológica, existem cinco variações: clássico, desmoplásico, anaplásico, células gigantes e de extensa nodularidade. Muitos estudos relatam que a patogênese do meduloblastoma está relacionada com mutações em fatores de crescimento do SNC, sendo que as principais vias envolvidas são: Sonic Hedgehog, NOTCH, WNT e OTX. Ainda, com respeito à imunologia, pacientes com meduloblastoma apresentaram alta taxa de IFN-γ no soro e células T H 17 no sangue periférico, e foi observado que o TGF-β tem sido associado à estimulação mitogênica, o que pode estar relacionado à patogênese da doença. A predominância de uma resposta T H 1 relacionada à sobrevivência também foi relatada. O desenvolvimento terapêutico para o meduloblastoma, apesar de limitado, é significativo, uma vez que este vem apresentando melhora na sobrevida de seus pacientes. Entretanto, um maior conhecimento dos mecanismos envolvidos na imunopatogênese é necessário para o desenvolvimento de novos fármacos e formas de tratamento. ResumoMedulloblastoma is a cerebellar tumor classified as primitive neuroectodermal tumor and is prevalent in children, especially male. With regard to histological classification, there are five variations: classical, desmoplastic, anaplastic, large-cell variant and with extensive nodularity. Several studies have reported that medulloblastoma pathogenesis is related to mutations in CNS growth factors, and the main pathways involved are Sonic Hedgehog, NOTCH, WNT, and OTX. Also regarding the immunology, patients with medulloblastoma have a high serum concentration of INF-γ and T H 17 cells in peripheral blood, and it Palavras-chave: Tumor cerebelar. Vias de sinalização. Imunopatologia.

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Diseases of Wnt signaling

Cited by 114 publications

References 96 publications

Wnt/β-Catenin Signaling Stimulates Chondrogenic and Inhibits Adipogenic Differentiation of Pericytes

Wnt/β-Catenin Signaling Stimulates Chondrogenic and Inhibits Adipogenic Differentiation of Pericytes

Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth

Meduloblastoma: aspectos histológicos, moleculares e imunopatológicos

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